Bendamustine and Lenalidomide in Relapsed/Refractory CLL

Front-line regimens for CLL typically include Fludarabine and Rituximab (R), producing ORRs of 90–95% (CR 44–47%) in multicenter trials. Despite these significant responses, patients (pts) invariably relapse and newer regimens are necessary for this relapsed/refractory population. Bendamustine (B) and Lenalidomide (L) have both shown efficacy as single agents in CLL with ORRs of 68–78% and 32–47%, respectively. The combination of these agents, however, has yet to be investigated. In this 2-stage phase I study, we are combining B and L in relapsed/refractory CLL (Stage I) in order to determine the MTD of L for future combination of BLR in CLL (Stage II). We report the preliminary results of the Stage I here.

Pts with relapsed/refractory CLL with adequate performance status and organ function were eligible. This phase I study utilized a standard 3 + 3 dose-escalation design. In Stage I all pts received L 5 mg po daily D-7 through D-1 and allopurinol 300 mg po daily D-2 to D14 of Cycle 1 to minimize the risk of tumor lysis syndrome (TLS). For each 28-day cycle, pts received B 90 mg/m² IV on D1, 2 with escalating doses of L po daily. Dose levels were 5 mg every other day (Cohort −1), 5 mg daily (Cohort 1), 10 mg daily (Cohort 2), 15 mg daily (Cohort 3), and 20 mg daily (Cohort 4). Pts in Cohorts 2 and higher received L 5 mg po daily during Cycle 1 followed by their respective cohort L doses in subsequent cycles. Pts received 6 cycles of BL followed by 6 cycles of L as long as tolerated or until disease progression.

For the 7 pts on study, the median age was 71 years, 100% were male, 43% were Rai Stage III/IV, 43% were CD38+, and 14% had a B-2 microglobulin level > 4. Two pts had sole del 13q, 3 had del 11q, and 1 had del 17p cytogenetics. Pts received a median of 1 prior therapy (range, 1–3). One pt had Richter’s transformation and one pt had PLL. The first pt (Richter’s transformation) in Cohort 1 had a DLT of Grade 3 rash. As rash is a common toxicity with L, the protocol was amended so that only Grade 3 rash that did not resolve to < Grade 2 within 10 days despite steroids or any Grade 4 rash were to be considered DLTs. In addition, L administration was reduced to only 21 days of each 28-day cycle. The trial was reinitiated after these amendments, and 3 new pts were enrolled into Cohort 1. There were no DLTs or Grade 3/4 rash found in this cohort. Three pts were enrolled into Cohort 2, but one suffered fatal septic shock during Cycle 2. No MTD has been reached for L. Common > Grade 3 toxicities included neutropenia (71%) and thrombocytopenia (29%). Pts completed a median of 5 cycles of therapy (range, 2–12). The most common reason for discontinuing therapy was toxicity. The ORR was 57% (CR of 14%). Responses were seen in pts with both sole del 13q and del 11q. The median time to response was 6 mos (range, 3–6 mos). Among the responders, the median length of response was 14 months (range, 13–23+ mo). Cohorts 1 and 2 have been completed.

BL demonstrates promising efficacy and tolerability in pts with relapsed/refractory CLL. Further evaluation is needed.

Cheson:Celphalon: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celegen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding.